Mechanisms for Increased Risk of Diabetes in Chronic Liver Diseases

Gianluca Svegliati-Baroni; Melania Gaggini; Fabrizia Carli; Chiara Barbieri; Monica Cucco; Ramy Youne; Chiara Rosso; Elisabetta Bugianesi; Amalia Gastaldelli


Liver International. 2020;40(10):2489-2499. 

In This Article

Abstract and Introduction


Objective: Patients with chronic liver disease (CLD), both non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC), are at high risk of diabetes (T2D), but mechanisms are still unknown. Muscle/liver insulin resistance (IR) and pancreatic dysfunction are the major metabolic defects leading to T2D. However, if the risk of T2D in CLD patients is because of reduced insulin response and/or to IR, and the impact of liver histology has not been investigated.

Design: We studied 220 non-T2D patients with chronic liver disease (129 NAFLD, BMI = 27.3 kg/m2; 91 CHC, BMI = 25.0 kg/m2) that received a 75-gram oral glucose tolerance test (OGTT) with the measurement of glucose and insulin concentrations for 2 hours, glucose tolerance (NGT vs IGT) and liver biopsy. The results were compared to 26 controls (CT-NGT, BMI = 25.6 kg/m2). We evaluated peripheral insulin sensitivity (OGIS), OGTT-insulin response (ΔAUC-I/ΔAUC-G) and disposition-index (DI = OGIS·ΔAUC-I/ΔAUC-G) for the risk to develop T2D.

Results: NAFLD had increased muscle IR (associated to NASH, steatosis and fibrosis), higher than in CHC or CT-NGT (OGIS = 8.9 vs 11.3 and 10.5 mL/min kg, P < .0001). In NAFLD, OGTT-insulin response (ΔAUC-I/ΔAUC-G) was the highest while it was significantly decreased in CHC (2.2 vs 1.1 and 1.6, NAFLD vs. CHC and CT-NGT, P < .005). The highest T2D risk (low DI) was observed in CHC-IGT (7.5), CHC-NGT (13.5) and NAFLD-IGT (10.8) vs CT-NGT (14.9, all P < .0001), but not in NAFL-NGT or NASH-NGT.

Conclusion: We observed an increased T2D risk in NAFLD-IGT, CHC-IGT and CHC-NGT mainly because of reduced OGTT-insulin response, while insulin response in NAFLD-NGT compensates the IR thus maintaining normal glycaemia.


In 2019, the global prevalence of type 2 diabetes (T2D) in adults aged 20–79 years was estimated to be 9.3%, but more importantly, more than half (50.1%) of subjects with T2D did not know to have the disease.[1] Chronic liver disease (CLD) is a major risk factor for decreased glucose tolerance and development of type 2 diabetes (T2D).[2–4] Among CLDs, non-alcoholic fatty liver disease (NAFLD) is now recognized as an emerging metabolic disease, associated with increased T2D risk and affecting almost 25% of the world population.[5] Similarly, but to a less extent, exposure to hepatitis C virus (HCV) represents a well-known risk factor for T2D.[6] Many studies have shown that all CLDs are associated with insulin resistance (IR)[7–9] although obesity is often not accounted as a covariate despite being an independent risk factor for IR and T2D. Moreover the impact of reduced β-cell function and insulin secretion on the risk of T2D in CLD is usually not investigated.

In the pathophysiology of T2D, not only IR but also pancreatic β-cell function and insulin secretion play a major role.[10–14] As subjects become insulin resistant (mainly in the periphery), their glucose tolerance is maintained until the amount of insulin secreted by the pancreas is no longer sufficient to overcome the muscle IR.[8,10,11,14] Both hepatic and pancreatic dysfunction are major defects that might explain the increased risk of T2D in subjects with liver disease. Alterations in hepatic glucose production and increased postprandial glycaemia are early signs of glucose intolerance[14] especially in patients with advanced liver disease even if they have normal fasting glucose concentrations (FPG).[15]

If and how IR and insulin secretion are altered in NAFLD and/or CHC patients is still unknown. The disposition index (DI, calculated from the insulin secretion factored by the insulin resistance) evaluates if the pancreatic insulin secretion is sufficient to overcome peripheral insulin resistance and maintain glycaemia within normal ranges.[10,16,17] Indeed, a low disposition index has been shown to be an independent marker of development of T2D.[17–20] However, to the best of our knowledge the disposition index has not been evaluated in patients with CLD diagnosed by liver biopsy. Moreover only few studies have investigated ß-cell function and insulin response to a glucose load in subjects with NAFLD or CHC.[15,21–25] Despite high hepatic fat accumulation and peripheral IR, ß-cell function was often found unaltered in NAFLD[21–23,25] indicating that most of the patients with CLD are able to compensate their IR by increasing insulin secretion and/or decreasing hepatic insulin clearance. Previously, Grancini et al have evaluated insulin secretion and ß-cell function in 160 advanced cirrhotic patients candidates for liver transplantation (the great majority with HCV) that underwent OGTT finding that insulin secretion worsens with the worsening of liver disease, and transition from IGT to DM is driven primarily by ß-cell dysfunction.[15] Narita et al have performed OGTT in patients with CHC but IR and ß-cell function were evaluated only according to glucose tolerance and not in relation to the histological severity of the disease.[24]

Here we evaluated if and how the type of CLD (NAFLD vs CHC) and severity of liver disease (degree of liver fibrosis) are associated to reduced peripheral insulin sensitivity and insulin response during an OGTT and how the increased risk of T2D of subjects with liver disease (evaluated by the disposition index) is related to alterations of the pancreas-liver cross-talk.